Viral sequences (virogenes) embedded in the mouse genome can direct the production of C-type RNA viruses. Although such endogenous virogenes are probably present in all mice, the specific pattern of virus production and associated disease is characteristic of a given inbred strain. Nucleic acid hybridization studies suggest this is at least partially due to quantitative and qualitative variation in the viral complement of different strains. The first goal of the proposed research is to define in molecular terms inbred strain variation in virogene organization. Specifically, studies will focus on the endogenous C-type virogenes of inbred strains AKR, which exhibits high susceptibility to leukemia, BALB/c, which exhibits low susceptibility to leukemia, and NZB, which suffers from autoimmune hemolytic anemia and immune-complex glomerulonephritis. All three possess ecotropic and xenotropic viral information within their genome although the first two produce ecotropic viruses predominantly while NZB apparently produces xenotropic virus exclusively. Comparison of gene organization will proceed in two stages. Restriction enzyme analysis will yield patterns of radioactive viral nucleic acid hybridization to genomic DNA restriction fragments after two dimensional fractionation of fragments by RPC-5 chromatography and agarose gelelectrophoresis. Virogene-containing fragments will then be cloned in the EK2-certified bacteriophage lambda gtWES - lambda B to allow sequencing and electron microscopic study of virogenes and their surrounding host sequences. Genetic studies have further identified strain-specific host factors that modulate virogene induction. The second goal of the proposed research is to define these host factors and their mode of action. These will be purified and characterized by assaying their effect on in vitro transcription and coupled transcription-translation of the cloned virogene-containing fragments. Ultimately, these studies should help to identify the critical elements responsible for the diseases characteristic of the AKR, BALB/c, and NZB strains.